The human papillomaviruses (HPVs) are associated with specific human cancers, most notably human cervical cancer. More than 70 different HPVs have now been described and approximately 25 of these are associated with lesions of the anogenital tract. These anogenital associated HPVs can be further subdivided into two groups on the basis of the clinical lesions with which they are associated. The "low risk" HPVs (e.g. HPV-6 and HPVI l) are associated with benign genital warts or condyloma acuminata that only very rarely progress to cancers, whereas the "high risk" HPVs (e.g. HPVI6 and HPVI8) are associated with intraepithelial neoplasias that can progress to cancer. Approximately 85-90% of human cervical cancers contain and viral DNA from a "high risk" HPV type and express the HPV E6 and E7 genes. This along with independent biochemical evidence, suggests strongly that the proteins encoded by the E6 and E7 genes of the "high risk" HPVs contribute directly to carcinogenic progression in the HPV positive cancers. The E7 proteins functions in cellular transformation, at least in part. through interactions with the product of the retinoblastoma susceptibility gene, pRB, and the other pRB related "pocket proteins". The major target of the E6 oncoprotein encoded by the genital tract, cancer associated human papillomaviruses is the p53 tumor suppressor protein. However, several lines of evidence indicate that the E6 protein of the cancer associated HPVs has additional cellular targets. Furthermore, the strongly oncogenic E6 protein encoded by the bovine papillomavirus does not cause transformation by a p53 dependent pathway. The specific aims of this grant proposal are designed to examine additional targets of the papillomavirtts E6 proteins that may be important to the transformation functions of the virus and to determine how the E6 interaction may affect the function of these cellular targets. We will determine the physiologic consequence of the interaction of E6 with the focal adhesion/LIM domain proteins paxillin and hic5. We will determine the consequences of the binding of HPV16 E6 to Interferon Regulatory Factor (IRF-3). Also we will determine the relevance of the binding of E6 to specific cellular targets to its transformation and tumorigenic functions.